Mushroom body subsets encode CREB2-dependent water-reward long-term memory in Drosophila

Autoři: Wang-Pao Lee aff001;  Meng-Hsuan Chiang aff001;  Li-Yun Chang aff001;  Jhen-Yi Lee aff002;  Ya-Lun Tsai aff001;  Tai-Hsiang Chiu aff001;  Hsueh-Cheng Chiang aff003;  Tsai-Feng Fu aff004;  Tony Wu aff005;  Chia-Lin Wu aff001
Působiště autorů: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taiwan aff001;  School of Medicine, College of Medicine, Chang Gung University, Taiwan aff002;  Department of Pharmacology, National Cheng-Kung University, Taiwan aff003;  Department of Applied Chemistry, National Chi Nan University, Taiwan aff004;  Department of Neurology, Chang Gung Memorial Hospital, Taiwan aff005;  Department of Biochemistry, College of Medicine, Chang Gung University, Taiwan aff006
Vyšlo v časopise: Mushroom body subsets encode CREB2-dependent water-reward long-term memory in Drosophila. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008963
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008963


Long-term memory (LTM) formation depends on the conversed cAMP response element-binding protein (CREB)-dependent gene transcription followed by de novo protein synthesis. Thirsty fruit flies can be trained to associate an odor with water reward to form water-reward LTM (wLTM), which can last for over 24 hours without a significant decline. The role of de novo protein synthesis and CREB-regulated gene expression changes in neural circuits that contribute to wLTM remains unclear. Here, we show that acute inhibition of protein synthesis in the mushroom body (MB) αβ or γ neurons during memory formation using a cold-sensitive ribosome-inactivating toxin disrupts wLTM. Furthermore, adult stage-specific expression of dCREB2b in αβ or γ neurons also disrupts wLTM. The MB αβ and γ neurons can be further classified into five different neuronal subsets including αβ core, αβ surface, αβ posterior, γ main, and γ dorsal. We observed that the neurotransmission from αβ surface and γ dorsal neuron subsets is required for wLTM retrieval, whereas the αβ core, αβ posterior, and γ main are dispensable. Adult stage-specific expression of dCREB2b in αβ surface and γ dorsal neurons inhibits wLTM formation. In vivo calcium imaging revealed that αβ surface and γ dorsal neurons form wLTM traces with different dynamic properties, and these memory traces are abolished by dCREB2b expression. Our results suggest that a small population of neurons within the MB circuits support long-term storage of water-reward memory in Drosophila.

Klíčová slova:

Calcium imaging – Conditioned response – Drosophila melanogaster – Memory – Neurons – Neurotransmission – Olfactory receptor neurons – Protein synthesis


1. Shyu WH, Chiu TH, Chiang MH, Cheng YC, Tsai YL, Fu TF, et al. Neural circuits for long-term water-reward memory processing in thirsty Drosophila. Nat Commun. 2017;8:15230. Epub 2017/05/16. doi: 10.1038/ncomms15230 28504254; PubMed Central PMCID: PMC5440665.

2. Davis HP, Squire LR. Protein synthesis and memory: a review. Psychol Bull. 1984;96(3):518–59. Epub 1984/11/01. 6096908.

3. Tully T, Preat T, Boynton SC, Del Vecchio M. Genetic dissection of consolidated memory in Drosophila. Cell. 1994;79(1):35–47. Epub 1994/10/07. 0092-8674(94)90398-0 [pii]. doi: 10.1016/0092-8674(94)90398-0 7923375.

4. Yin JCP, Tully T. CREB and the formation of long-term memory. Curr Opin Neurobiol. 1996;6(2):264–8. doi: 10.1016/s0959-4388(96)80082-1 WOS:A1996UN15100016. 8725970

5. Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell. 2014;157(1):163–86. Epub 2014/04/01. doi: 10.1016/j.cell.2014.03.001 24679534.

6. Yin JC, Wallach JS, Del Vecchio M, Wilder EL, Zhou H, Quinn WG, et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell. 1994;79(1):49–58. Epub 1994/10/07. 0092-8674(94)90399-9 [pii]. doi: 10.1016/0092-8674(94)90399-9 7923376.

7. Perazzona B, Isabel G, Preat T, Davis RL. The role of cAMP response element-binding protein in Drosophila long-term memory. J Neurosci. 2004;24(40):8823–8. doi: 10.1523/JNEUROSCI.4542-03.2004 15470148.

8. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994;79(1):59–68. Epub 1994/10/07. doi: 10.1016/0092-8674(94)90400-6 7923378.

9. Krashes MJ, Waddell S. Rapid consolidation to a radish and protein synthesis-dependent long-term memory after single-session appetitive olfactory conditioning in Drosophila. J Neurosci. 2008;28(12):3103–13. Epub 2008/03/21. 28/12/3103 [pii] doi: 10.1523/JNEUROSCI.5333-07.2008 18354013; PubMed Central PMCID: PMC2516741.

10. Dash PK, Hochner B, Kandel ER. Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature. 1990;345(6277):718–21. Epub 1990/06/21. doi: 10.1038/345718a0 2141668.

11. Lin S, Owald D, Chandra V, Talbot C, Huetteroth W, Waddell S. Neural correlates of water reward in thirsty Drosophila. Nat Neurosci. 2014;17(11):1536–42. Epub 2014/09/30. doi: 10.1038/nn.3827 25262493; PubMed Central PMCID: PMC4213141.

12. Honegger KS, Campbell RA, Turner GC. Cellular-resolution population imaging reveals robust sparse coding in the Drosophila mushroom body. J Neurosci. 2011;31(33):11772–85. Epub 2011/08/19. doi: 10.1523/JNEUROSCI.1099-11.2011 21849538; PubMed Central PMCID: PMC3180869.

13. Turner GC, Bazhenov M, Laurent G. Olfactory representations by Drosophila mushroom body neurons. J Neurophysiol. 2008;99(2):734–46. doi: 10.1152/jn.01283.2007 18094099

14. Aso Y, Grubel K, Busch S, Friedrich AB, Siwanowicz I, Tanimoto H. The mushroom body of adult Drosophila characterized by GAL4 drivers. J Neurogenet. 2009;23(1–2):156–72. Epub 2009/01/14. doi: 10.1080/01677060802471718 19140035.

15. Aso Y, Hattori D, Yu Y, Johnston RM, Iyer NA, Ngo TT, et al. The neuronal architecture of the mushroom body provides a logic for associative learning. Elife. 2014;3. Epub 2014/12/24. doi: 10.7554/eLife.04577 25535793.

16. Endo Y, Mitsui K, Motizuki M, Tsurugi K. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. The site and the characteristics of the modification in 28 S ribosomal RNA caused by the toxins. J Biol Chem. 1987;262(12):5908–12. Epub 1987/04/25. 3571242.

17. Endo Y, Tsurugi K. RNA N-glycosidase activity of ricin A-chain. Mechanism of action of the toxic lectin ricin on eukaryotic ribosomes. J Biol Chem. 1987;262(17):8128–30. Epub 1987/06/15. 3036799.

18. Chen CC, Wu JK, Lin HW, Pai TP, Fu TF, Wu CL, et al. Visualizing long-term memory formation in two neurons of the Drosophila brain. Science. 2012;335(6069):678–85. Epub 2012/02/11. doi: 10.1126/science.1212735 22323813.

19. Davis RL. Traces of Drosophila memory. Neuron. 2011;70(1):8–19. Epub 2011/04/13. doi: 10.1016/j.neuron.2011.03.012 21482352.

20. Yu D, Akalal DB, Davis RL. Drosophila alpha/beta mushroom body neurons form a branch-specific, long-term cellular memory trace after spaced olfactory conditioning. Neuron. 2006;52(5):845–55. Epub 2006/12/06. S0896-6273(06)00830-0 [pii] doi: 10.1016/j.neuron.2006.10.030 17145505; PubMed Central PMCID: PMC1779901.

21. Akalal DB, Yu D, Davis RL. A late-phase, long-term memory trace forms in the gamma neurons of Drosophila mushroom bodies after olfactory classical conditioning. J Neurosci. 2010;30(49):16699–708. Epub 2010/12/15. doi: 10.1523/JNEUROSCI.1882-10.2010 21148009; PubMed Central PMCID: PMC3380342.

22. Wang Y, Mamiya A, Chiang AS, Zhong Y. Imaging of an early memory trace in the Drosophila mushroom body. J Neurosci. 2008;28(17):4368–76. Epub 2008/04/25. 28/17/4368 [pii] doi: 10.1523/JNEUROSCI.2958-07.2008 18434515.

23. Shyu WH, Lee WP, Chiang MH, Chang CC, Fu TF, Chiang HC, et al. Electrical synapses between mushroom body neurons are critical for consolidated memory retrieval in Drosophila. PLoS Genet. 2019;15(5):e1008153. Epub 2019/05/10. doi: 10.1371/journal.pgen.1008153 31071084; PubMed Central PMCID: PMC6529013.

24. Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Ann Rev Neurosci. 1998;21:127–48. doi: 10.1146/annurev.neuro.21.1.127 WOS:000072446400006. 9530494

25. Widmer YF, Fritsch C, Jungo MM, Almeida S, Egger B, Sprecher SG. Multiple neurons encode CrebB dependent appetitive long-term memory in the mushroom body circuit. Elife. 2018;7. Epub 2018/10/23. doi: 10.7554/eLife.39196 30346271; PubMed Central PMCID: PMC6234028.

26. Senapati B, Tsao CH, Juan YA, Chiu TH, Wu CL, Waddell S, et al. A neural mechanism for deprivation state-specific expression of relevant memories in Drosophila. Nat Neurosci. 2019;22(12):2029–39. Epub 2019/10/30. doi: 10.1038/s41593-019-0515-z 31659341.

27. Krashes MJ, DasGupta S, Vreede A, White B, Armstrong JD, Waddell S. A neural circuit mechanism integrating motivational state with memory expression in Drosophila. Cell. 2009;139(2):416–27. Epub 2009/10/20. S0092-8674(09)01105-2 [pii] doi: 10.1016/j.cell.2009.08.035 19837040; PubMed Central PMCID: PMC2780032.

28. Cervantes-Sandoval I, Martin-Pena A, Berry JA, Davis RL. System-like consolidation of olfactory memories in Drosophila. J Neurosci. 2013;33(23):9846–54. Epub 2013/06/07. doi: 10.1523/JNEUROSCI.0451-13.2013 23739981; PubMed Central PMCID: PMC3733538.

29. Trannoy S, Redt-Clouet C, Dura JM, Preat T. Parallel processing of appetitive short- and long-term memories in Drosophila. Curr Biol. 2011;21(19):1647–53. Epub 2011/10/04. doi: 10.1016/j.cub.2011.08.032 21962716.

30. Huang C, Wang P, Xie Z, Wang L, Zhong Y. The differential requirement of mushroom body alpha/beta subdivisions in long-term memory retrieval in Drosophila. Protein Cell. 2013;4(7):512–9. Epub 2013/06/01. doi: 10.1007/s13238-013-3035-8 23722532; PubMed Central PMCID: PMC4875512.

31. Perisse E, Yin Y, Lin AC, Lin S, Huetteroth W, Waddell S. Different kenyon cell populations drive learned approach and avoidance in Drosophila. Neuron. 2013;79(5):945–56. Epub 2013/09/10. doi: 10.1016/j.neuron.2013.07.045 24012007; PubMed Central PMCID: PMC3765960.

32. Qin H, Cressy M, Li W, Coravos JS, Izzi SA, Dubnau J. Gamma neurons mediate dopaminergic input during aversive olfactory memory formation in Drosophila. Curr Biol. 2012;22(7):608–14. Epub 2012/03/20. doi: 10.1016/j.cub.2012.02.014 22425153; PubMed Central PMCID: PMC3326180.

33. Waddell S, Armstrong JD, Kitamoto T, Kaiser K, Quinn WG. The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory. Cell. 2000;103(5):805–13. Epub 2000/12/15. S0092-8674(00)00183-5 [pii]. doi: 10.1016/s0092-8674(00)00183-5 11114336.

34. Wu CL, Shih MF, Lai JS, Yang HT, Turner GC, Chen L, et al. Heterotypic gap junctions between two neurons in the Drosophila brain are critical for memory. Curr Biol. 2011;21(10):848–54. Epub 2011/05/03. doi: 10.1016/j.cub.2011.02.041 21530256.

35. Wu CL, Shih MF, Lee PT, Chiang AS. An octopamine-mushroom body circuit modulates the formation of anesthesia-resistant memory in Drosophila. Curr Biol. 2013;23(23):2346–54. Epub 2013/11/19. doi: 10.1016/j.cub.2013.09.056 24239122.

36. Takemura SY, Aso Y, Hige T, Wong A, Lu Z, Xu CS, et al. A connectome of a learning and memory center in the adult Drosophila brain. Elife. 2017;6. Epub 2017/07/19. doi: 10.7554/eLife.26975 28718765; PubMed Central PMCID: PMC5550281.

37. Wu CL, Fu TF, Chou YY, Yeh SR. A single pair of neurons modulates egg-laying decisions in Drosophila. PLoS One. 2015;10(3):e0121335. Epub 2015/03/18. doi: 10.1371/journal.pone.0121335 25781933; PubMed Central PMCID: PMC4363143.

38. Haynes PR, Christmann BL, Griffith LC. A single pair of neurons links sleep to memory consolidation in Drosophila melanogaster. Elife. 2015;4. Epub 2015/01/08. doi: 10.7554/eLife.03868 25564731; PubMed Central PMCID: PMC4305081.

39. Keene AC, Stratmann M, Keller A, Perrat PN, Vosshall LB, Waddell S. Diverse odor-conditioned memories require uniquely timed dorsal paired medial neuron output. Neuron. 2004;44(3):521–33. Epub 2004/10/27. S0896627304006476 [pii] doi: 10.1016/j.neuron.2004.10.006 15504331.

40. Keene AC, Krashes MJ, Leung B, Bernard JA, Waddell S. Drosophila dorsal paired medial neurons provide a general mechanism for memory consolidation. Curr Biol. 2006;16(15):1524–30. Epub 2006/08/08. S0960-9822(06)01707-6 [pii] doi: 10.1016/j.cub.2006.06.022 16890528.

41. Aso Y, Sitaraman D, Ichinose T, Kaun KR, Vogt K, Belliart-Guerin G, et al. Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila. eLife. 2014;4. Epub 2015/01/03. doi: 10.7554/eLife.04580 25553800.

42. Vogt K, Aso Y, Hige T, Knapek S, Ichinose T, Friedrich AB, et al. Direct neural pathways convey distinct visual information to Drosophila mushroom bodies. Elife. 2016;5. Epub 2016/04/16. doi: 10.7554/eLife.14009 27083044; PubMed Central PMCID: PMC4884080.

43. Shih HW, Wu CL, Chang SW, Liu TH, Sih-Yu Lai J, Fu TF, et al. Parallel circuits control temperature preference in Drosophila during ageing. Nat Commun. 2015;6:7775. Epub 2015/07/17. doi: 10.1038/ncomms8775 26178754; PubMed Central PMCID: PMC4518306.

44. Yang CH, Shih MF, Chang CC, Chiang MH, Shih HW, Tsai YL, et al. Additive expression of consolidated memory through Drosophila mushroom body subsets. PLoS Genet. 2016;12(5):e1006061. Epub 2016/05/20. doi: 10.1371/journal.pgen.1006061 27195782.

45. Wu CL, Chang CC, Wu JK, Chiang MH, Yang CH, Chiang HC. Mushroom body glycolysis is required for olfactory memory in Drosophila. Neurobiol Learn Mem. 2018;150:13–9. doi: 10.1016/j.nlm.2018.02.015 WOS:000431470600002. 29477608

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